An
old complication, a new cause?

Lipoatrophy virtually disappeared as a cutaneous complication of insulin
therapy after the introduction of recombinant human insulin. Consequently, we
were surprised to observe two cases of marked lipoatrophy occurring in
patients treated by lispro insulin administered by continuous subcutaneous
insulin infusion (CSII).

The first case is a 10-year-old Caucasian girl diagnosed with type 1
diabetes at 4 years of age. HbA1c levels had ranged between 7.8 and
8.7% (normal ≤6.3%) on two daily injections of human NPH and regular
insulin (Humulin-Regular; Eli Lilly, Indianapolis, IN) with ultralente (Eli
Lilly) added subsequently. Apart from mild lipohypertrophy of the biceps area,
there were no cutaneous complications. At 8 years of age, increased
HbA1c levels and several severe hypoglycemic episodes prompted a
switch to CSII (MiniMed model 507) using lispro insulin (Humulog; Eli Lilly),
35-40 U daily, 60% as basal replacement. HbA1c levels fell to
6.5-7.2%, and there were no further episodes of hypoglycemia. Twelve months
after commencing pump therapy, lipoatrophy was noted in the subcutaneous
tissues of the anterior abdominal wall and progressed over the next few
months. Treatment was changed from lispro to buffered human regular insulin
(Velosulin; Novo Nordisk, Princeton, NJ). There has been no further
progression of skin lesions, although the lipoatrophic areas have persisted
(Fig. 1).

The second case is a 51-year-old Caucasian woman who was diagnosed with
type 1 diabetes at 12 years of age and began CSII with buffered human regular
insulin (Velosulin; Novo Nordisk) in 1996 (HbA1c 8.1%). Previous
treatment with prebreakfast injection of beef-pork NPH and regular insulin had
resulted in no cutaneous complications. Ischemic heart disease, elevated LDL
cholesterol, primary hypothyroidism, background of mild retinopathy, and
distal sensory neuropathy were present. In 1998, treatment was changed to
lispro insulin (Humulog; Eli Lilly) and HbA1c levels were between
5.5 and 6.4%. In the summer of 1999, she noticed lipoatrophy in the abdomen
and thigh, and her bolus doses before meals were taking longer to peak, even
when bolus was administered into nonaffected areas. Examination revealed
lipoatrophy involving the abdominal wall, lateral thighs, and buttocks, all of
which were sites of previous insulin infusions.

These cases highlight a potential for lispro insulin to induce lipoatrophy.
While CSII may have contributed to the problem, use of lispro appears to be
the most important factor. No further progression in lipoatrophy was noted in
either patient after the switch to buffered human regular insulin using the
same MiniMed pump systems. Moreover, one author (W.V.T.) met a teenage girl at
a symposium who developed lipoatrophy with lispro delivered by a Disetronic
pump.

Lipoatrophy in the era of less highly purified insulins was considered to
have an immunologic basis. However, Fineberg et al.
(1) have reported no
differences in immunogenicity between lispro and recombinant human insulin.
Nevertheless, lispro has proved to be an effective substitute for human
regular insulin in several cases of presumed immunogenic insulin resistance
(2,3,4).
Thus, the mechanism causing lipoatrophy in our patients is unclear.

The purpose of this letter is to alert clinicians to a potential
complication of lispro insulin not previously published or reported to Eli
Lilly during premarketing or postmarketing studies (J. Holcombe, personal
communication). Fortunately, this adverse effect appears to be uncommon and
readily managed by switching to human regular insulin. It would be important
to determine whether others have observed similar problems and whether these
problems are limited to CSII.